Influenza is a highly contagious disease caused by infection of the respiratory tract with influenza virus. It can cause potentially life-threatening complications especially in infants and the elderly.
Protection against re-infection with homologous virus is mediated primarily by neutralizing antibodies, but recovery from influenza virus infections requires cytotoxic CD8+ T (Tc) cell responses. Current vaccines against influenza virus are predominantly inactivated whole virus or subunit preparations, where the infectivity of the virus is inactivated by chemical treatment. These vaccines function almost exclusively by inducing neutralising antibodies targetting viral surface glycoproteins subject to frequent antigenic variation (e.g. HA and NA). The frequent antigenic variation exhibited by viral surface glycoproteins means that vaccines directed against them do not elicit a broadly cross-reactive immune response and are thus unable to protect against multiple influenza virus subtypes and strains. The protective value of antibody-based vaccines is thus restricted in that little or no protective immunity is provided against new subtypes/strains arising from frequent antigenic drift and/or shift of influenza viruses. Furthermore, the selective pressures imparted on viral surface glycoproteins by such vaccines serve to enhance antigenic variation rendering the vaccines ineffective.
The formulation of current influenza vaccines is based on “educated guesses” made by comparing currently circulating human influenza strains to known isolates. However, the prediction of influenza strain/s that may cause infection in a given flu season can not accommodate for the expected antigenic variability arising due to viral mutations. Moreover, while ongoing virus mutations and associated antigenic variation decreases the efficacy of vaccines, incorrect prediction renders the vaccine ineffective. The northern hemisphere flu vaccine formulation for season 2007-2008 (A/Solomon Islands/3/2006 (H1N1)-like virus; A/Wisconsin/67/2005 (H3N2)-like virus; and B/Malaysia/2506/2004-like virus) illustrates such a scenario. According to the Centers for Disease Control and Prevention in the U.S., Type A H3N2 Brisbane strain and Type B Florida strain were responsible for most of the illnesses in that flu season, however those strains were not incorporated into the vaccine which was consequently ineffective.
The beneficial affects of vaccination induced T cell-mediated immunity in ameliorating the severity of influenza has been largely ignored. The T cell response is central to successful recovery from primary infections with influenza and reduces disease severity by lowering the viral burden early after infection. T cell immunity is also long-lasting, and the antigenic determinants involved in eliciting T cell responses are generally derived from conserved proteins (e.g. viral nucleoprotein and matrix proteins) that are usually not subject to immune evasion by the virus. Hence, vaccines capable of eliciting T-cell mediated immunity are desirable and this need is not met by currently available inactivated influenza vaccine preparations.
Moreover, methods used in the manufacture of currently available influenza vaccines involve harsh treatments that compromise the integrity of viral antigens. For example, ultracentrifugation has a damaging effect on viral antigens but is commonly used to purify virus prior to attenuation. Furthermore, chemically inactivated influenza vaccine preparations require the use of unfrozen virus allowing physical and chemical agents to damage antigenic proteins. Therefore, viral inactivation methods effective on frozen virus preparations offer the advantage of limiting antigen degradation which enhances immunogenicity.
A need exists for influenza vaccines capable of inducing T lymphocyte responses. In particular, a need exists for influenza vaccines capable of inducing cross-protective immunity to influenza viruses, regardless of surface antigen variability frequently arising from antigenic shift and/or drift.